Ligand Specificity in Fragment-Based Drug Design

Abstract

Fragment-based drug design consists of identifying low-molecular weight compounds that weakly bind to a target macromolecule and will then be modified or linked to yield potent inhibitors. The specificity of these low-complexity and low-affinity molecules has rarely been discussed in the literature. To address this question, NMR spectroscopy was used to investigate the interactions of 150 fragments with five proteins: three proteins from the Bcl-2 family (Bcl-x(L), Bcl-w, and Mcl-1), human peroxiredoxin 5, for which very few ligands have been reported, and human serum albumin, which is known to bind a large number of ligands. Our results show that the fragments are rather versatile binders and able to identify binding hot spots in very different targets. Despite the different hit rates observed related to the druggability of the proteins, two scaffolds appear as preferred binders for all proteins. Low specificity was observed between homologous proteins or unrelated poorly druggable proteins, while higher specificity could be achieved with highly druggable targets.

Integrated biophysical approach to fragment screening and validation for fragment-based lead discovery

“…This hit rate includes both true and false hits. A low hit rate does not reflect a limitation of the technique, but rather the potential druggability and stability of the target being investigated (42) or even the design of the library used (43).…”

Computational and Experimental Prediction of Human C-Type Lectin Receptor Druggability

“…Hence, sensitive biophysical techniques are necessary to monitor this interaction and nuclear magnetic resonance (NMR) spectroscopy has established itself as one of the major techniques used for fragment screening (31, 33, 37–39, 44, 45). In particular, hit rates from NMR-based screenings have proven to be reliable measures of druggability (31, 37, 44). In ligand-observed NMR, mixtures of fragments are screened against a target and changes in NMR observables such as chemical shift, line width, and signal intensity upon binding allow hit identification.…”

Le criblage de fragments

“…Les fragments qui apparaissent comme touches dans les expériences de criblage sont ensuite validés un par un par différentes approches RMN (Figure 4). La RMN présente aussi l'avantage d'être une méthode structurale, ce qui nous permet non seulement de cribler les fragments, mais aussi d'intervenir dans la sélection des fragments touches, dans leur optimisation et leur évolution en molécules « tête de série », en s'aidant de données structurales concernant le complexe protéine-fragment [19][20][21][22][23][24][25].…”